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The Centre for Evidence-Based Medicine (CEBM) at Oxford University develops, promotes and disseminates better evidence for health care.
The PRINCIPLE randomised controlled open label platform trial of hydroxychloroquine for treating COVID19 in community based patients at high risk
Early on in the COVID-19 pandemic, we aimed to assess the effectiveness of hydroxychloroquine on reducing the need for hospital admission in patients in the community at higher risk of complications from COVID-19 syndromic illness (testing was largely unavailable at the time, hence not microbiologically confirmed SARS-CoV-2 infection), as part of the national open-label, multi-arm, prospective, adaptive platform, randomised clinical trial in community care in the United Kingdom (UK). People aged 65 and over, or aged 50 and over with comorbidities, and who had been unwell for up to 14 days with suspected COVID-19 were randomised to usual care with the addition of hydroxychloroquine, 200 mg twice a day for seven days, or usual care without hydroxychloroquine (control). Participants were recruited based on symptoms and approximately 5% had confirmed SARS-COV2 infection. The primary outcome while hydroxychloroquine was in the trial was hospital admission or death related to suspected COVID-19 infection within 28 days from randomisation. First recruitment was on April 2, 2020, and the hydroxychloroquine arm was suspended by the UK Medicines Regulator on May 22, 2020. 207 were randomised to hydroxychloroquine and 206 to usual care, and 190 and 194 contributed to the primary analysis results presented, respectively. There was no swab result available within 28 days of randomisation for 39% in both groups: 107 (54%) in the hydroxychloroquine group and 111 (55%) in the usual care group tested negative for SARS-Cov-2, and 13 (7%) and 11 (5%) tested positive. 13 participants, (seven (3·7%) in the usual care plus hydroxychloroquine and six (3.1%) in the usual care group were hospitalized (odds ratio 1·04 [95% BCI 0·36 to 3.00], probability of superiority 0·47). There was one serious adverse event, in the usual care group. More people receiving hydroxychloroquine reported nausea. We found no evidence from this treatment arm of the PRINCIPLE trial, stopped early and therefore under-powered for reasons external to the trial, that hydroxychloroquine reduced hospital admission or death in people with suspected, but mostly unconfirmed COVID-19.
Crafting Tempo and Timeframes in Qualitative Longitudinal Research: Case Studies From Health Research
Qualitative Longitudinal Research (QLR) is a dynamic and evolving methodology using time as a lens to inform study design, data collection and analysis. A key feature of QLR is the collection of data on more than one occasion, often described as waves or time points. Thus, researchers embarking on designing a new study need to consider several key features including the study duration (timeframe) and the frequency and intensity of data collection (tempo). Yet, how to embed these features in practice is not well described. Leveraging the intensive-extensive temporal plane of time, we explore research approaches employing both shorter and longer timeframes, as well as intensive and extensive tempos. Drawing on six studies that we have conducted, we discuss four pivotal aspects including: (i) crafting intensive-extensive tempo and timeframes; (ii) defining baseline and closure points; (iii) planning for flexibility; and (iv) working ethically within a temporal lens. By examining and critically analysing these case studies through the lens of the intensive-extensive plane of time, this article aspires to offer insights for researchers interested in using the QLR design in healthcare. We thus aim to prepare researchers for embedding these features during the research process.
Implementing a text message-based intervention to support type 2 diabetes medication adherence in primary care: a qualitative study with general practice staff
Background: The Support through Mobile Messaging and digital health Technology for Diabetes (SuMMiT-D) project has developed, and is evaluating, a mobile phone-based intervention delivering brief messages targeting identified behaviour change techniques promoting medication use to people with type 2 diabetes in general practice. The present study aimed to inform refinement and future implementation of the SuMMiT-D intervention by investigating general practice staff perceptions of how a text message-based intervention to support medication adherence should be implemented within current and future diabetes care. Methods: Seven focus groups and five interviews were conducted with 46 general practice staff (including GPs, nurses, healthcare assistants, receptionists and linked pharmacists) with a potential role in the implementation of a text message-based intervention for people with type 2 diabetes. Interviews and focus groups were audio-recorded, transcribed and analysed using an inductive thematic analysis approach. Results: Five themes were developed. One theme ‘The potential of technology as a patient ally’ described a need for diabetes support and the potential of technology to support medication use. Two themes outlined challenges to implementation, ‘Limited resources and assigning responsibility’ and ‘Treating the patient; more than diabetes medication adherence’. The final two themes described recommendations to support implementation, ‘Selling the intervention: what do general practice staff need to see?’ and ‘Fitting the mould; complementing current service delivery’. Conclusions: Staff see the potential for a text message-based support intervention to address unmet needs and to enhance care for people with diabetes. Digital interventions, such as SuMMiT-D, need to be compatible with existing systems, demonstrate measurable benefits, be incentivised and be quick and easy for staff to engage with. Interventions also need to be perceived to address general practice priorities, such as taking a holistic approach to care and having multi-cultural reach and relevance. Findings from this study are being combined with parallel work with people with type 2 diabetes to ensure stakeholder views inform further refinement and implementation of the SuMMiT-D intervention.
Exploring the variation in muscle response testing accuracy through repeatability and reproducibility
Research Objectives To explore the variation in mean muscle response testing (MRT) accuracy and whether this variation can be attributable to participant characteristics. Methods A prospective study of diagnostic test accuracy was carried out in a round-robin format. Sixteen practitioners tested each of 7 test patients (TPs) using 20 MRTs broken into 2 blocks of 10 which alternated with 2 blocks of 10 intuitive guessing. Mean MRT accuracies (as overall percent correct) were calculated for each unique pair. Reproducibility and repeatability were assessed using analyses of variance (ANOVA) and scatter and Bland-Altman plots. Results The mean MRT accuracy (95% CI) was 0.616 (0.578–0.654), which was significantly different from both the mean intuitive guessing accuracy, 0.507 (95% CI 0.484–0.530; p<0.01) and chance (p<0.01). Visual inspection of scatterplots of mean MRT accuracies by practitioner and by TP suggest large variances among both subsets, and regression analysis revealed that MRT accuracy could not be predicted by TP (r = ‒0.14; p = 0.19), nor by Practitioner (r = 0.01; p = 0.90). A significant effect imposed by both practitioners and TPs individually and together was found at the p<0.05 level; however, together they account for only 57.0% of the variance, with 43.0% of the variance unexplained by this model. From a statistical perspective, Bland-Altman Plots of mean MRT accuracy by practitioner do show adequate repeatability since all scores fell within 2 SDs of the mean; however, the wide range of scores also suggests insufficient repeatability from a clinical perspective. Finally, ANOVA demonstrated that an insignificant amount of variance could be explained by block [F(1,21) = 0.02, p=0.90].
Leadership training in healthcare: a systematic umbrella review.
The importance of effective clinical leadership has been reflected in an increase in leadership development programmes. However, there remains a lack of consensus regarding the optimal structure, content and evaluation of such programmes. This review synthesised evidence from reviews of leadership development interventions for healthcare professionals published prior to October 2024, including content, methods, evaluation strategies and impact. Title, abstract and full-text screening were conducted in duplicate by two reviewers. Data extraction was piloted by two reviewers and conducted by a single reviewer. Quality appraisal was conducted using the Risk of Bias in Systematic Reviews tool by a single reviewer, with generative artificial intelligence serving as the second reviewer. 86 systematic and non-systematic reviews met inclusion criteria. Regarding educational methods, leadership training effectiveness was associated with experiential learning, mixed-methods approaches, coaching or mentoring, longitudinal designs, goal-setting, and 360-degree feedback. Group learning and interprofessional education were noted for fostering teamwork. Programmes tailored to participants' needs and organisational contexts showed better outcomes. Content reported to be effective included interpersonal skills, self-awareness, emotional intelligence, leadership theory, communication and teamwork. Evaluations primarily relied on self-reported measures. Training outcomes were largely positive at the individual level, with participants reporting increased confidence and competence. Organisational and clinical outcomes were less frequently assessed. The long-term impact on patient outcomes and return on investment remains uncertain. Leadership development programmes were found to enhance individual competencies. However, evidence supporting long-term, system-wide impact remains limited due to reliance on self-reported evaluations and a lack of standardised evaluation approaches.
Assessing the feasibility and impact of clinical trial trustworthiness checks via an application to Cochrane Reviews: Stage 2 of the INSPECT-SR project
Background and Objectives: The aim of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is to develop a tool to identify problematic RCTs in systematic reviews. In stage 1 of the project, a list of potential trustworthiness checks was created. The checks on this list must be evaluated to determine which should be included in the INSPECT-SR tool. Methods: We attempted to apply 72 trustworthiness checks to randomized controlled trials (RCTs) in 50 Cochrane reviews. For each, we recorded whether the check was passed, failed, or possibly failed or whether it was not feasible to complete the check. Following application of the checks, we recorded whether we had concerns about the authenticity of each RCT. We repeated each meta-analysis after removing RCTs flagged by each check and again after removing RCTs where we had concerns about authenticity to estimate the impact of trustworthiness assessment. Trustworthiness assessments were compared to Risk of Bias and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments in the reviews. Results: Ninety-five RCTs were assessed. Following application of the checks, assessors had some or serious concerns about the authenticity of 25% and 6% of the RCTs, respectively. Removing RCTs with either some or serious concerns resulted in 22% of meta-analyses having no remaining RCTs. However, many checks proved difficult to understand or implement, which may have led to unwarranted skepticism in some instances. Furthermore, we restricted assessment to meta-analyses with no more than five RCTs (54% contained only 1 RCT), which will distort the impact on results. No relationship was identified between trustworthiness assessment and Risk of Bias or GRADE. Conclusion: This study supports the case for routine trustworthiness assessment in systematic reviews, as problematic studies do not appear to be flagged by Risk of Bias assessment. The study produced evidence on the feasibility and impact of trustworthiness checks. These results will be used, in conjunction with those from a subsequent Delphi process, to determine which checks should be included in the INSPECT-SR tool. Plain Language Summary: Systematic reviews collate evidence from randomized controlled trials (RCTs) to find out whether health interventions are safe and effective. However, it is now recognized that the findings of some RCTs are not genuine, and some of these studies appear to have been fabricated. Various checks for these “problematic” RCTs have been proposed, but it is necessary to evaluate these checks to find out which are useful and which are feasible. We applied a comprehensive list of “trustworthiness checks” to 95 RCTs in 50 systematic reviews to learn more about them and to see how often performing the checks would lead us to classify RCTs as being potentially inauthentic. We found that applying the checks led to concerns about the authenticity of around 1 in three RCTs. However, we found that many of the checks were difficult to perform and could have been misinterpreted. This might have led us to be overly skeptical in some cases. The findings from this study will be used, alongside other evidence, to decide which of these checks should be performed routinely to try to identify problematic RCTs, to stop them from being mistaken for genuine studies and potentially being used to inform health care decisions.
The impact of inter-infection time on antimicrobial resistance profiles in women with multiple urinary tract infections over time.
BACKGROUND: Urinary tract infection (UTI) treatment in primary care is increasingly complicated by antimicrobial resistance (AMR), and antimicrobial susceptibility profiles are rarely available to prescribers at the point of prescription. Susceptibility profiles from previous urine culture results could inform prescribing, but little is known about associations between previous and current susceptibilities and the impact of time between infections (inter-infection time) on these associations. METHODS: We analysed routinely collected healthcare records of women ≥16 years in Oxfordshire, UK, who had two or more culture-positive urine specimens consistent with a UTI between 2013 and 2019. We used generalized additive logistic models to estimate associations between resistance to each of eight commonly prescribed antibiotics at first UTI and at second UTI, and their interaction with inter-infection time, adjusted for age and calendar year. RESULTS: In 10 216 women, significant associations were observed between AMR at first and second UTIs. For all antibiotics, these were largest for short inter-infection times. Pivmecillinam resistance at first UTI (OR: 41.70; 95% CI: 27.70-62.80), followed by fosfomycin (OR: 19.90; CI: 13.66-28.92) and ciprofloxacin resistance (OR: 19.65; 95% CI: 16.30-23.75), were strongly associated with resistance to the same antibiotic at the second UTI for inter-infection times ≤3 months. Lower magnitude associations were observed for other antibiotics. For UTIs caused by Escherichia coli only, these associations were generally larger. CONCLUSIONS: In a cohort of women experiencing UTIs, AMR at the first UTI and inter-infection time were key determinants of AMR in the second UTI. This information could inform empirical antimicrobial treatment to limit treatment failure in women with recurrent UTI.
Epidemiology and microbiology of recurrent UTI in women in the community in Oxfordshire, UK
Background: Recurrent urinary tract infection (rUTI) contributes to significant morbidity and antibiotic usage. Objectives: To characterize the age of women experiencing rUTI, the microbiology of rUTIs, and the risk of further rUTIs in Oxfordshire, UK. Patients and methods: We retrospectively analysed de-identified linked microbiology and hospital admissions data (Infections in Oxfordshire Research Database), between 2008 and 2019, including positive urine cultures from women aged ≥16 years in community settings. We defined rUTI as ≥2 positive urine cultures within 6 months or ≥3 within 12 months. Results: Of 201 927 women with urine culture performed, 84 809 (42%) had ≥1 positive culture, and 15 617 (18%) of these experienced ≥1 rUTI over a median (IQR) follow-up of 6 (3-9) years. Women with rUTI were 17.0 (95% CI: 16.3-17.7) years older on average. rUTI was commonest (6204; 40%) in those aged 70-89 years. Post-rUTI, the risk of further UTI within 6 months was 29.4% (95% CI: 28.7-30.2). Escherichia coli was detected in 65% of positive cultures. Among rUTIs where the index UTI was E. coli associated, the second UTI was also E. coli associated in 81% of cases. Conclusions: rUTIs represent a substantial healthcare burden, particularly in women >60 years. One-third of women experiencing rUTI have a further microbiologically confirmed UTI within 6 months.
Risk of repeat self-harm among individuals presenting to healthcare services: development and validation of a clinical risk assessment model (OxSET)
Background A self-harm episode is a major risk factor for repeat self-harm. Existing tools to assess and predict repeat self-harm have major methodological limitations, and few are externally validated. Objective To develop and validate a risk assessment model of repeat self-harm up to 6 months after an episode of non-fatal self-harm that resulted in an emergency visit to hospital or specialised care. Methods Using Swedish national registers, we identified 53 172 people aged≥10 years who self-harmed during 2008–2012. We allocated 37 523 individuals to development (2820 or 7.5% repeat self-harm incidents within 6 months) and 15 649 to geographic validation (1373 repeat episodes) samples, based on region of residence. In a temporal validation of people who self-harmed during 2018–2019, we identified 25 036 individuals (2886 repeat episodes). We fitted a multivariable accelerated failure time model to predict risk of repeat self-harm. Findings In the external validations (n=40 685), rates of repeat self-harm were 8.8%–11.5% over 6 months. The final model retained 17 factors. Calibration and discrimination were similar in both validation samples, with observed-to-expected ratio=1.15 (95% CI=1.09 to 1.21) and c-statistic=0.72 (95% CI=0.70 to 0.73) in the geographical validation. At 6 months and a 10% risk cutoff, sensitivity was 51.5% (95% CI=48.8% to 54.2%) and specificity was 80.7% (95% CI=80.1% to 81.4%) in geographic validation; corresponding values were 56.9% (95% CI=55.1% to 58.7%) and 76.0% (95% CI=75.5% to 76.6%) in temporal validation. Discrimination was slightly worse at the 1-month prediction horizon (c-statistics of 0.66–0.68). Conclusions Using mostly routinely collected data, simple risk assessment models and tools can provide acceptable levels of accuracy for repeat of self-harm. Clinical implications This risk model (OXford SElf-harm repeat tool) may assist clinical decision-making.
Impact and outcomes of the Emerging Leaders Programme: A mixed-methods evaluation of a leadership development programme for healthcare professionals
Background: The significance of effective medical leadership in enhancing healthcare outcomes has been widely acknowledged. This study evaluates the Emerging Leaders Programme, a multidisciplinary leadership development initiative for healthcare professionals at a UK Hospital Trust. Methods: The evaluation spanned three cohorts (2017-2019) and a total of 54 participants, employing mixed methods to assess participant reactions, learning, behaviour changes and organisational impact. Quantitative pre-/post-measures included the Primary Colours Questionnaire (PCQ), Medical Leadership Competency Framework Questionnaire (MLCFQ) and Brief Resilience Scale (BRS), while qualitative data were gathered via free-text comments and long-term follow-up interviews. Results: The programme had high satisfaction ratings, with particularly positive feedback relating to the multidisciplinary cohort and experiential learning via Quality Improvement projects. Findings indicated improvements in participants' leadership skills, knowledge, confidence and job satisfaction. Organisational outcomes included increased organisational interest in quality improvement and individual career progression. Conclusion: The results highlight the value of a structured leadership programme in developing healthcare leaders and driving organisational improvements, with long-term effects. Recommendations for future programmes include multidisciplinary involvement, experiential learning, inspiring speakers and embedded mixed-methods evaluation.
Risk of death by suicide following self-harm presentations to healthcare: development and validation of a multivariable clinical prediction rule (OxSATS)
BACKGROUND: Assessment of suicide risk in individuals who have self-harmed is common in emergency departments, but is often based on tools developed for other purposes. OBJECTIVE: We developed and validated a predictive model for suicide following self-harm. METHODS: We used data from Swedish population-based registers. A cohort of 53 172 individuals aged 10+ years, with healthcare episodes of self-harm, was split into development (37 523 individuals, of whom 391 died from suicide within 12 months) and validation (15 649 individuals, 178 suicides within 12 months) samples. We fitted a multivariable accelerated failure time model for the association between risk factors and time to suicide. The final model contains 11 factors: age, sex, and variables related to substance misuse, mental health and treatment, and history of self-harm. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines were followed for the design and reporting of this work. FINDINGS: An 11-item risk model to predict suicide was developed using sociodemographic and clinical risk factors, and showed good discrimination (c-index 0.77, 95% CI 0.75 to 0.78) and calibration in external validation. For risk of suicide within 12 months, using a 1% cut-off, sensitivity was 82% (75% to 87%) and specificity was 54% (53% to 55%). A web-based risk calculator is available (Oxford Suicide Assessment Tool for Self-harm or OxSATS). CONCLUSIONS: OxSATS accurately predicts 12-month risk of suicide. Further validations and linkage to effective interventions are required to examine clinical utility. CLINICAL IMPLICATIONS: Using a clinical prediction score may assist clinical decision-making and resource allocation.
Variation in duration of repeat prescriptions: a primary care cohort study in England
Background Many patients receive repeat prescriptions for routine medications used to treat chronic conditions. Doctors typically issue repeat prescriptions with durations ranging from 28 to 84 days. There is currently no national guidance in England for the optimal prescription duration for routine medications. Aim To evaluate current prescription durations for five common routine medications in England; explore and visualise geographical variation; and identify practice factors that are associated with shorter prescribing duration to inform policy making. Design and setting A retrospective cohort study of NHS primary care prescribing data in England from December 2018 to November 2019. Method The prescription duration was analysed for five common routine medications in England; ramipril, atorvastatin, simvastatin, levothyroxine, and amlodipine. Variation was assessed between regional clinical commissioning groups (CCGs), and practice factors associated with different durations were identified. Results Of the common medications included, 28-day prescriptions accounted for 48.5% (2.5 billion) tablets/ capsules issued, while 43.6% were issued for 56 days. There was very wide regional variation (7.2%–95.0%) in the proportion of 28-day prescriptions issued by CCGs. Practice dispensing status was the most likely predictor of prescription duration; dispensing practices had a higher 28-day prescribing proportion than non-dispensing practices. The proportion of patients with chronic conditions and the electronic health record system used by a practice were also associated with prescription duration. Conclusion This analysis of OpenPrescribing data showed that repeat prescriptions of 28 days are common for patients taking routine medications for chronic conditions, particularly in dispensing practices. This provides data to inform the policy debate on current practice. Configuration of electronic health record systems offer an opportunity to implement and evaluate new policies on repeat prescription duration in England.
UMBRELLA protocol: systematic reviews of multivariable biomarker prognostic models developed to predict clinical outcomes in patients with heart failure.
BACKGROUND: Heart failure (HF) is a chronic and common condition with a rising prevalence, especially in the elderly. Morbidity and mortality rates in people with HF are similar to those with common forms of cancer. Clinical guidelines highlight the need for more detailed prognostic information to optimise treatment and care planning for people with HF. Besides proven prognostic biomarkers and numerous newly developed prognostic models for HF clinical outcomes, no risk stratification models have been adequately established. Through a number of linked systematic reviews, we aim to assess the quality of the existing models with biomarkers in HF and summarise the evidence they present. METHODS: We will search MEDLINE, EMBASE, Web of Science Core Collection, and the prognostic studies database maintained by the Cochrane Prognosis Methods Group combining sensitive published search filters, with no language restriction, from 1990 onwards. Independent pairs of reviewers will screen and extract data. Eligible studies will be those developing, validating, or updating any prognostic model with biomarkers for clinical outcomes in adults with any type of HF. Data will be extracted using a piloted form that combines published good practice guidelines for critical appraisal, data extraction, and risk of bias assessment of prediction modelling studies. Missing information on predictive performance measures will be sought by contacting authors or estimated from available information when possible. If sufficient high quality and homogeneous data are available, we will meta-analyse the predictive performance of identified models. Sources of between-study heterogeneity will be explored through meta-regression using pre-defined study-level covariates. Results will be reported narratively if study quality is deemed to be low or if the between-study heterogeneity is high. Sensitivity analyses for risk of bias impact will be performed. DISCUSSION: This project aims to appraise and summarise the methodological conduct and predictive performance of existing clinically homogeneous HF prognostic models in separate systematic reviews.Registration: PROSPERO registration number CRD42019086990.